Dynamic change, influencing factors, and clinical impact of cellular components in human breast milk.

BACKGROUND: Numerous cellular components have been well demonstrated in human breast milk. However, little is known about their dynamic change, influencing factors, and potential clinical impacts on infants. METHODS: Sixty and forty-five healthy mother-infant pairs were enrolled in the colostrum group and mature milk group, respectively. Participants' demographic and clinical information were collected by questionnaires, and the infants were followed up until 6 months after birth through telephone interview. Colostrum and mature milk were collected, and the percentage of various cell components were determined by flow cytometric analysis. RESULTS: The results showed that, the total cell numbers, and the percentages of some stem cells, including CD34+, CD117+, CD133+, CD90+, CD105+, and CD146+ cells, were different in colostrum and mature milk. Besides, participants' characteristics had influence on the cellular components. Finally, high-CD34+ cells in colostrum, as well as the high-CD133+ cells and low-CD105+ cells in mature milk were associated with a significantly increased risk of infantile eczema within their first 3 months after birth. CONCLUSIONS: Our data showed a dynamic change of cellular components, identified some of their influencing factors and their potential clinical impacts on infantile eczema, which helps to better understand the cellular components in human breast milk. IMPACT: Some stem cell markers were dynamically changed in human colostrum and mature milk. Different cellular components were shown to be influenced by different participants' characteristics. High percentage of CD34+ cells in colostrum, as well as high percentage of CD133+ cells and low percentage of CD105+ cells in mature milk, were associated with a significantly increased risk of infantile eczema within their first 3 months after birth. To our knowledge, this is the first study on the clinical impacts of stem cells on infantile diseases, which helps to give a better understanding of human breast milk.

Clinical Manifestation of Hyper IgE Syndrome Including Otitis Media.

PURPOSE OF REVIEW: The hyper IgE syndromes (HIES) comprise a group of rare primary immunodeficiency disorders (PIDDs), which are characterized by extremely high serum IgE levels, eczema, recurrent skin and pulmonary infections. Both autosomal dominant (AD) HIES due to STAT3 mutations and autosomal recessive (AR) HIES due to PGM3, SPINK5, DOCK8 and TKY2 mutations have been reported. Here, we aim to summarize and compare the major clinical manifestations of different subtypes of HIES. We will also discuss otitis media, which usually do not get enough attention in HIES. Update and familiarity with these clinical features will help to make a better diagnose, assessment and treatment of HIES. RECENT FINDINGS: Although hyper serum IgE levels have been identified in PGM3 deficiency and Comel-Netherton syndrome, PGM3 and SPINK5 genes were not included in the list of genetic etiologies of AR-HIES by the Expert Committee of the International Union of Immunological Societies until 2015. The identification of these HIES-causing genes greatly promoted the pathogenic mechanism studies of HIES. Also, in recent years, more clinical manifestations, which were often not of concern in HIES patients, have been shown to be highly related to HIES. For example, a significantly high frequency of vascular and gastrointestinal abnormities has been reported in STAT3-deficient AD-HIES patients. These new findings might help to provide new clues to the functional study of these HIES-related genes. This review summarizes and compares the major clinical manifestations of different subtypes of HIES, and we suggest that the incidence and severity of otitis media should not be underestimated in HIES patients.

Serum IP-10 is useful for identifying renal and overall disease activity in pediatric systemic lupus erythematosus.

BACKGROUND: Traditional serological biomarkers often fail to assess systemic lupus erythematosus (SLE) disease activity and discriminate lupus nephritis (LN). The aim of this study was to identify novel markers for evaluating renal and overall disease activity in Chinese patients with pediatric systemic lupus erythematosus (pSLE). METHODS: The study included 46 patients with pSLE (35 girls, 11 boys; average age 13.3 ± 2.6 years) and 31 matched healthy controls (22 girls, 9 boys; average age 12.3 ± 2.4 years). The SLE Disease Activity Index (SLEDAI) and renal SLEDAI were used to assess disease activity. Nine different soluble mediators in plasma, including tumor necrosis factor alpha (TNF-α), platelet-derived growth factor-BB (PDGF-BB), interferon (IFN) gamma inducible protein 10 (IP-10), interleukin (IL)-1ß, IFN-γ, IL-17A, IL-2, Fas and Fas ligand, were measured by Luminex assay and compared between patients with active and inactive pSLE as well as between patients with pSLE with active and inactive renal disease. Receiver operating characteristic curve analysis was used to measure the discrimination accuracy. RESULTS: Of the 46 patients with pSLE, 30 (65.2%) had LN. These patients had significantly elevated levels of serum TNF-α, PDGF-BB, IP-10 and Fas. The serum levels of IP-10 were also significantly higher in patients with active pSLE. We found that IP-10 was also more sensitive and specific than conventional laboratory parameters, including anti-double-stranded DNA and complement components C3 and C4, for distinguishing active lupus from quiescent lupus. The serum level of IP-10 was also significantly increased in children with pSLE with active renal disease relative to those with inactive renal disease. There was also a positive correlation between serum IP-10 levels and renal SLEDAI scores as well as with 24 h urine protein. CONCLUSIONS: Serum IP-10 is useful for identifying renal and overall disease activity in children with pSLE.

Clinical Manifestations and Genetic Analysis of 17 Patients with Autosomal Dominant Hyper-IgE Syndrome in Mainland China: New Reports and a Literature Review.

PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare complicated primary immunodeficiency disease (PID). Signal transducer and activator of transcription 3 (STAT3) gene mutation is found to cause AD-HIES. The distribution of AD-HIES patients with STAT3 deficiency in the Chinese population is not clear. Herein, we retrospectively report 17 AD-HIES patients with STAT3 deficiency and demonstrate their clinical, immunological, and genetic features. METHODS: Patients' clinical data were collected from their medical records. Routine laboratory testing results included lymphocyte subset analysis and immunoglobulin quantification. STAT3 mutations were investigated by sequencing of genomic DNA. RESULTS: Among 575 patients with PID, 28 (4.87%) were clinically diagnosed as HIES. Among them, 17 (2.96%) were confirmed as STAT3 mutant AD-HIES. The ratio of male to female patients was 8:9. All of the 17 patients had NIH scores over 40 points. The mean ages at onset and diagnosis were 1.05 and 10.35 years, respectively. Three patients (17.65%, 3/17) died with a mean age of 13.33 years. Eczema, recurrent skin infection, and respiratory tract infection were the most common clinical symptoms and are present in all of the 17 patients in this study. Six patients (37.5%, 6/16) suffered complication from BCG vaccination. Noninfection symptoms are characteristic facial features in 17 patients (100%, 17/17), retention of primary teeth in 10 patients (90.91%, 10/11), and abnormal bone fractures in 7 patients (41.18%, 7/17). Eleven types of STAT3 mutations were identified in 17 patients, including 1 novel mutation. CONCLUSIONS: We here retrospectively report the largest Chinese cohort of AD-HIES patients with STAT3 mutation. Unique features, when compared to existing literature reports, include (1) later age of diagnosis, (2) significantly higher rate of BCG complications, and (3) lower rate of candidiasis and chronic otitis media.

[Positive allergens in children with different allergic diseases].

OBJECTIVE: To investigate the major allergens in children with different allergic diseases, and to provide theoretical evidence for the clinical prevention, diagnosis, and treatment of allergic diseases in children. METHODS: Skin prick test (SPT) was conducted to detect allergens in 1179 allergic children. According to clinical diagnoses, patients were categorized into six groups: atopic dermatitis (n=140), allergic gastroenteritis (n=37), allergic conjunctivitis (n=77), asthma (n=285), allergic rhinitis (n=301) and allergic co-morbidity (n=329) groups. RESULTS: Of the 1179 patients, 82.0% had positive SPT results; the most prevalent inhalant allergens were Dermatophagoides farinae (68.1%) and Dermatophagoides pteronyssinus (53.5%), while the most common food allergens were milk (5.0%) and eggs (4.8%). The proportions were 84.3% and 83.8% for patients under or equal to 3 years of age in the atopic dermatitis and allergic gastroenteritis groups, respectively. Patients over 4 years of age accounted for the majority of the other four groups. Food as major allergens were found in both atopic dermatitis and allergic gastroenteritis groups; eggs and Dermatophagoides farinae were the most common allergens for the former group, while eggs and milk for the latter group. Inhalant allergens were the major allergens in the allergic conjunctivitis, allergic rhinitis, asthma, and allergic co-morbidity groups, and the most prevalent allergens were Dermatophagoides farinae and Dermatophagoides pteronyssinus. CONCLUSIONS: There are differences in the distribution of age and allergen types in children with different allergic diseases. Atopic dermatitis and allergic gastroenteritis are prevalent in infants and young children, and food allergens are more common. Patients in allergic conjunctivitis, allergic rhinitis, asthma, and allergic co-morbidity groups are mostly children over 4 years of age, and inhalant allergens are more common.

Identification of sociodemographic and clinical factors associated with the levels of human ß-defensin-1 and human ß-defensin-2 in the human milk of Han Chinese.

Human milk provides infants with various immune molecules. The objective of the present study was to measure human ß-defensin-1 (hBD-1) and human ß-defensin-2 (hBD-2) levels in the colostrum and mature milk of healthy Han Chinese, to identify factors regulating milk hBD-1 and hBD-2 expression and to explore the potential protective effect of milk hBD-1 and hBD-2 on infants. A total of 100 mothers and their babies were recruited into the study. Sociodemographic characteristics and other factors were obtained by a questionnaire. Babies were followed up for a period of 6 months. Colostrum samples (n 100) and mature milk samples (n 82) were collected by hand expression. The hBD-1 and hBD-2 concentrations were measured by ELISA. The hBD-1 and hBD-2 levels differed in the colostrum and mature milk. In the colostrum, the concentration ranges of hBD-1 and hBD-2 were 1·04-12·81 µg/ml and 0·31-19·12 ng/ml, respectively. In mature milk, the hBD-1 and hBD-2 levels were 1·03-31·76 ng/ml and 52·65-182·29 pg/ml, respectively. Several independent factors influence their production. The multivariable analysis showed a strong association between pre-pregnancy BMI and hBD-1 levels in the colostrum (P=0·001), mode of delivery was significantly associated with hBD-2 levels in the colostrum (P=0·006) and gestational age was significantly associated with hBD-1 levels in mature milk (P= 0·010). During the first 6 months of life, the incidence rate of upper respiratory infection was found to be less in the high-colostrum hBD-1 group than in the low-colostrum hBD-1 group (χ²=4·995, P=0·025). The present study suggested that the abundance of hBD-1 in the colostrum may have a protective function against upper respiratory infection for infants younger than 6 months.

Clinical characteristics and genetic profiles of 44 patients with severe combined immunodeficiency (SCID): report from Shanghai, China (2004-2011).

Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.

Exploring dynamic change and influencing factors of TGF-ß1 and MUC1 in human breast milk, and their association with infantile diseases.

Background: Human breast milk, which comprises numerous bioactive compositions, has been well-demonstrated to be benefit to the infants in both short-term and long-term outcomes. We aim to determine the concentration of transforming growth factor beta 1 (TGF-ß1) and mucin 1 (MUC1) in human breast milk, identify their influencing factors, and explore their association with infantile diseases. Methods: Ninety paired mother-infants were enrolled in this study, and their demographic and clinical information was collected and analyzed. Paired colostrum and mature milk samples were collected from the healthy mothers within 5 days and at about 42 days after delivery, respectively. The concentrations of TGF-ß1 and MUC1 were determined by enzyme-linked immunosorbent assay. Results: The results showed that the concentrations of TGF-ß1 and MUC1 in human breast milk dynamically changed during lactation, and their concentrations were significantly higher in colostrum than in mature milk. Advanced maternal age was associated with a significantly increased TGF-ß1 concentration in colostrum, and caesarean delivery was significantly associated with an increased MUC1 concentration in colostrum. Finally, a high concentration of TGF-ß1 in colostrum was significantly associated with a higher risk of infantile diarrhea within the first 3 months after giving birth, and infantile upper respiratory infection (URI) within the first 6 months after giving birth. Conclusions: To the best of our knowledge, we for the first time showed that a high concentration of TGF-ß1 in human breast milk was significantly associated with an increased risk of infantile diarrhea and URI, which helps to give a better understanding of the relationship between the TGF-ß1 in human breast milk and infantile diseases.

Genome-Wide ChIP-seq and RNA-seq Analyses of STAT3 Target Genes in TLRs Activated Human Peripheral Blood B Cells.

Toll like receptors (TLRs) induced response plays a vital role in B-cell development and activation, in which TLR7-mediated and TLR9-mediated response interact together and play antagonistic or cooperative roles at different situations. Previous studies showed that the transcription factor signal transducer and activator of transcription (STAT) 3 was one of the key transcriptional factors (TFs) needed for both TLR7 and TLR9 signaling in B cell, and patients with autosomal dominant hyper IgE syndromes (AD-HIES) due to STAT3 mutations having defective TLRs response in B cells. However, how STAT3 affects its target genes and the downstream signaling pathways in B cell upon TLRs stimulation remains unclarified on a genome-wide level. ChIP-seq and RNA-seq was used in this study to identify the STAT3 targets in response to TLRs stimulation in human B cell. STAT3 ChIP-seq results showed a total of 611 and 2,289 differential STAT3-binding sites in human B cell after TLR7 and TLR9 agonists stimulation, respectively. RNA-seq results showed 1,186 and 1,775 differentially expressed genes after TLR7 and TLR9 activation, respectively. We identified 47 primary STAT3 target genes after TLR7 activation and 189 target genes after TLR9 activation in B cell by integration of STAT3 ChIP-seq and RNA-seq data. Among these STAT3 primary targets, we identified 7 TFs and 18 TFs for TLR7 and TLR9 response, respectively. Besides, we showed that STAT3 might regulate TLR9, but not TLR7 response in B cells through directly regulating integrin signaling pathway, which might further affect the antagonism between TLR7 and TLR9 signaling in B cell. Our study provides insights into the molecular mechanism of human TLRs response in B cell and how it can be regulated, which helps to better understand and modulate TLR-mediated pathogenic immune responses in B cell.

Targeted Gene Sanger Sequencing Should Remain the First-Tier Genetic Test for Children Suspected to Have the Five Common X-Linked Inborn Errors of Immunity.

To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott-Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.

Distribution and clinical features of primary immunodeficiency diseases in Chinese children (2004-2009).

Two hundred and one patients have been diagnosed with primary immunodeficiency diseases (PIDs) in our center from January 2004 to December 2009. The male-to-female ratio was 5.29:1. Spectrums of PIDs were as follows: predominantly antibody deficiency disease was the most common category (94 patients, 48.2%), followed by other well-defined immunodeficiency syndromes (40 patients, 20.5%), combined T and B cell immunodeficiencies (33 patients, 16.9%), congenital defects of phagocyte number and/or function (21 patients, 10.8%), and diseases of immune dysregulation (six patients, 3.1%). Agammaglobulinemia was the most frequent disease type. The median of diagnosis lag was 18.0 months. Pneumonia was the most common manifestation of PID patients. Some manifestations were prone to concentrate in certain diseases. As for therapy, 99 patients (50.8%) received intravenous immunoglobulin replacement therapy; 13 patients received hematopoietic stem cell transplantation and nine of them were still alive. In this study, we sought to describe and analyze the distribution, clinical features, and therapy methods of PIDs among children diagnosed in our country and to compare with reports from other countries and regions.

Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children.

Severe combined immunodeficiencies (SCID) are a group of rare inherited disorders with profound defects in T cell and B cell immunity. From 2005 to 2010, our unit performed testing for IL2RG, JAK3, IL7R, RAG1, RAG2, DCLRE1C, LIG4, AK2, and ZAP70 mutations in 42 Chinese and Southeast Asian infants with SCID adopting a candidate gene approach, based on patient's gender, immune phenotype, and inheritance pattern. Mutations were identified in 26 patients, including IL2RG (n = 19), IL7R (n = 2), JAK3 (n = 2), RAG1 (n = 1), RAG2 (n = 1), and DCLRE1C (n = 1). Among 12 patients who underwent hematopoietic stem cell transplantation, eight patients survived. Complications and morbidities during transplant period were significant, especially disseminated bacillus Calmette-Guérin disease which was often difficult to control. This is the first cohort study on SCID in the Chinese and Southeast Asian population, based on a multi-centered collaborative research network. The foremost issue is service provision for early detection, diagnosis, management, and definitive treatment for patients with SCID. National management guidelines for SCID should be established, and research into an efficient platform for genetic diagnosis is needed.

Partially hydrolyzed cow's milk formula has a therapeutic effect on the infants with mild to moderate atopic dermatitis: a randomized, double-blind study.

OBJECTIVE: The allergy-preventing effect of partially hydrolyzed cow's milk formula (phCMF) in infants at high risk of atopic dermatitis (AD) has been demonstrated in many studies. However, the therapeutic potential of phCMF in treating the infants with AD has not been reported. We sought to assess such therapeutic efficacy of phCMF in infants with mild to moderate AD. METHODS: From 2006 to 2008, 113 infants <6 months of age with AD were randomized to receive either partially hydrolyzed cow's milk formula (phCMF) or conventional cow's milk formula (CMF) in a double-blind clinical trial. Assessments were made at enrollment and at weeks 4, 8, and 12. The severity of AD was assessed using two scoring systems: Standard guideline for management (diagnosis, severity scoring, and therapy) of AD by the Japanese Dermatological Association Scoring System (JDASS) and the SCORing Atopic Dermatitis (SCORAD). Growth status of the infants was evaluated. Allergy profile was assessed by measuring total blood eosinophils (EOS), total/specific IgE, Th1/Th2 cytokine profiles, and the percentage of regulatory T cells. RESULTS: After follow-up for 12 wk, 27 infants (23.89%) dropped off study. Analysis was performed on 86 infants by the end of 12-wk observation. The AD severity scores were significantly reduced in the phCMF group (n = 56) compared with CMF group (n = 30) after 12 wk (p < 0.05). The severity scores of phCMF group were significantly reduced at weeks 4, 8, and 12 compared to enrollment (p < 0.05). In contrast, no significant improvement was observed for CMF group at any of those time points (p > 0.05). The number of AD flare-ups was significantly decreased in the phCMF group (p = 0.002). Th1/Th2 ratio in phCMF was significantly increased compared with CMF group (p = 0.041). The growth rates did not differ significantly between these feeding groups at any assessed time point (p > 0.05) and were in the normal range. CONCLUSION: This study suggests a novel therapeutic effect of phCMF in treating infants with mild to moderate AD during the first 6 months of their life without affecting their nutritional status.

Role of SOCS3 in enhanced acute-phase protein genes by neonatal macrophages in response to IL-6.

BACKGROUND: Interleukin 6 (IL-6) induce the inflammatory response directly related with the morbidity and mortality of neonatal. Here we aimed to explore the mechanism of IL-6 in neonatal inflammatory response by studying the IL-6/STAT3 signaling pathway. METHODS: Cord blood samples from health term neonatal and peripheral venous blood from health volunteers were collected. The monocytes of adults and cord blood were isolated and induced into macrophages. Then the macrophages were pretreated with or without MG132 before IL-6 stimulation. Proteins were analyzed by Western blot, mRNA by real time PCR and membrane molecule by flow cytometry. RESULTS: The acute phase protein gene expression in neonatal macrophages after stimulated with IL-6 were higher than that in adult. Significantly enhanced phosphorylation of STAT3 was seen in neonatal macrophages. Both mRNA and protein expression of SOCS3 in neonatal macrophages were lower than that in adult. After pretreated with MG132, the expression of SOCS3 protein was increased which lead to attenuate the STAT3 phosphorylation and APP gene expression. CONCLUSION: Neonatal exhibit an enhanced expression of downstream target genes and IL-6/STAT3 signal pathway which is related with the diminished SOCS3. This provides a new sight into inflammatory responses in neonatal.

The effects of a biodegradable Mg-based alloy on the function of VSMCs via immunoregulation of macrophages through Mg-induced responses.

BACKGROUND: Restenosis is one of the worst side effects of percutaneous coronary intervention (PCI) due to neointima formation resulting from the excessive proliferation and migration of vascular smooth muscle cells (VSMCs) and continuous inflammation. Biodegradable Mg-based alloy is a promising candidate material because of its good mechanical properties and biocompatibility, and biodegradation of cardiovascular stents. Although studies have shown reduced neointima formation after Mg-based CVS implantation in vivo, these findings were inconsistent with in vitro studies, demonstrating magnesium-mediated promotion of the proliferation and migration of VSMCs. Given the vital role of activated macrophage-driven inflammation in neointima formation, along with the well-demonstrated crosstalk between macrophages and VSMCs, we investigated the interactions of a biodegradable Mg-Nd-Zn-Zr alloy (denoted JDBM), which is especially important for cardiovascular stents, with VSMCs via macrophages. METHODS: JDBM extracts and MgCl2 solutions were prepared to study their effect on macrophages. To study the effects of the JDBM extracts and MgCl2 solutions on the function of VSMCs via immunoregulation of macrophages, conditioned media (CM) obtained from macrophages was used to establish a VSMC-macrophage indirect coculture system. RESULTS: Our results showed that both JDBM extracts and MgCl2 solutions significantly attenuated the inflammatory response stimulated by lipopolysaccharide (LPS)-activated macrophages and converted macrophages into M2-type cells. In addition, JDBM extracts and MgCl2 solutions significantly decreased the expression of genes related to VSMC phenotypic switching, migration, and proliferation in macrophages. Furthermore, the proliferation, migration, and proinflammatory phenotypic switching of VSMCs were significantly inhibited when the cells were incubated with CMs from macrophages treated with LPS + extracts or LPS + MgCl2 solutions. CONCLUSIONS: Taken together, our results suggested that the magnesium in the JDBM extract could affect the functions of VSMCs through macrophage-mediated immunoregulation, inhibiting smooth muscle hyperproliferation to suppress restenosis after implantation of a biodegradable Mg-based stent.

Phenomic Analysis of Chronic Granulomatous Disease Reveals More Severe Integumentary Infections in X-Linked Compared With Autosomal Recessive Chronic Granulomatous Disease.

Background: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI), characterised by recurrent bacterial and fungal infections. It is inherited either in an X-linked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of phenotypes expressed, and its study allows us to generate new knowledge of the disease. The objective of the study is to reveal the phenomic differences between XL and AR-CGD by using Human Phenotype Ontology (HPO) terms. Methods: We collected data on 117 patients with genetically diagnosed CGD from Asia and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only 90 patients with sufficient clinical information were included for phenomic analysis. We used HPO terms to describe all phenotypes manifested in the patients. Results: XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and genetic diagnosis compared with AR-CGD patients. The integument and central nervous system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as their first manifestation. Among our CGD patients, lung was the most frequently infected organ, with gastrointestinal system and skin ranking second and third, respectively. Aspergillus species, Mycobacterium bovis, and Mycobacteirum tuberculosis were the most frequent pathogens to be found. Conclusion: Phenomic analysis confirmed that XL-CGD patients have more recurrent and aggressive infections compared with AR-CGD patients. Various phenotypic differences listed out can be used as clinical handles to distinguish XL or AR-CGD based on clinical features.

Clinical characteristics and genotype-phenotype correlation in 62 patients with X-linked agammaglobulinemia.

INTRODUCTION: X-linked agammagobulinemia (XLA) is a primary immunodeficiency disorder caused by Bruton's tyrosine kinase (Btk) gene mutation. Recent studies suggested genotype-phenotype correlation in XLA, but a definitive association remains controversial. PATIENTS AND METHODS: We examined the relationship between specific Btk gene mutations and severity of clinical presentation in 62 patients with XLA. Disease severity was assessed by the age of disease onset and the presence of severe infections, while mutations were classified into severe and mild based on structural and functional consequence by bioinformatics analysis. RESULTS: Fifty-six Btk mutations were identified in 62 patients from 57 kindreds. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset as well as occurrence of severe infections. CONCLUSION: A critical analysis of the circumstances upon presentation also revealed that under-recognition of recurrent infections and relevant family history are important hurdles to timely diagnosis of XLA.

The role of the lactadherin in promoting intestinal DCs development in vivo and vitro.

Lactadherin, as one of the immune components in the breast milk, might play a role in the intestinal immune system of newborn. Therefore, we investigated the effect of lactadherin-feeding in early time on the development of intestinal immune system compared with naturally rearing and artificially rearing (non-lactadherin). In the present study, we observed that the Peyer's Patches (PP) from the pups of artificially reared group with lactadherin added were characterized by an excess of OX62(+)CD4(+)SIRP(+) DC cells and a higher expression of CD3(+)CD4(+)CD25(+)T cells. Additionally, this study also demonstrated that IL-10 production was dramatically increased when lactadherin was present in culture medium compared with lactadherin-absent culture. These results suggested that lactadherin could adjust intestinal DCs activity, induce CD3(+)CD4(+)CD25(+)T cell differentiation, and enhance IL-10 production.

Clinical and molecular characteristics of 35 Chinese children with Wiskott-Aldrich syndrome.

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency disease, with an incidence of 4/1,000,000 live male births. In China, an estimated number of 35 babies with WAS are born each year, but likely many remain undiagnosed. OBJECTIVES: The objectives of study were to review the clinical and molecular characteristics of a cohort of Chinese children with WAS and to describe the long-term outcome of those who underwent hematopoietic stem cell transplant (HSCT). MATERIALS AND METHOD: Records of 35 patients diagnosed with WAS during 1991-2008 were reviewed. Genetic diagnosis was established by direct gene sequencing. RESULTS: All patients had classical WAS phenotype. WASP mutations were identified in 33 patients from 29 families. Nine patients underwent HSCT at a mean age of 22.1 months (match-unrelated donor, n = 5; mismatched related donor, n = 2; matched-sibling donor, n = 2). Post-transplant immune hemolytic anemia and thrombocytopenia occurred in three patients with complete resolution. All patients survived without significant long-term complications and had full platelet, T and B lymphocyte recovery within 2 years post-transplant. CONCLUSION: In the past decade, there has been significant improvement in clinical and genetic diagnosis of WAS in Chinese. We demonstrated excellent long-term survival in patients who underwent HSCT. Early workup for transplant should be advocated for children with classical WAS before they suffer from major disease complications and morbidities.